Method for synthesizing aryl hydrazine through reduction of a diazo compound derivative

ABSTRACT

The invention involves a procedure for synthesizing aryl hydrazine through reduction of a diazo derivative. The distinguishing feature of the method is that it involves at least the following step: c) bringing a diazo derivative into contact with a sulphite solution in which the pH level is at least 7. Applications: organic synthesis.

The present invention relates to a process for the synthesis ofarylhydrazine or a derivative thereof by reduction of a diazoderivative. The invention relates more particularly to a bisulphite-typereduction.

The most direct route of access to hydrazines substituted with an arylderivative is, in most cases, the diazotation of an aniline, followed bya reduction, generally a hydrogenation.

Besides being relatively expensive, this route has many difficulties,among which mention may be made of the often prohibitive number of stepsand the formation of heavy by-products, resulting, ipso facto, in verymediocre overall yield and purity. On top of all this, the reductiontechniques give erratic results, depending on the substituents on therings. The problem is particularly pronounced in the case ofelectron-poor aromatic rings.

Thus, in the course of the study which led to the present invention, ithas been shown that the most standard technique for reducing "diazo"compounds, i.e. the use of tin, gives results which, at best, can onlybe described as mediocre.

Accordingly, one of the aims of the present invention is to provide aprocess which makes it possible to obtain arylhydrazine from a diazoderivative.

Another aim of the present invention is to provide a process which issuitable for electron-poor or moderately electron-poor rings.

Another aim of the present invention is to provide a process whichallows a good yield.

Another aim of the present invention is to provide a process whichallows the one-step production of arylhydrazines which can readily bepurified or which can even be obtained directly in high purity.

These aims and others which will become apparent hereinbelow areachieved by means of a process for reducing a diazo derivative, thisprocess including at least the following step:

c) placing the diazo derivative in contact with a sulphite solutionwhose pH is at least equal to 7.

The reason for this is that the use of sulphite has proved to beparticularly advantageous as a reducing agent provided that it is at asufficiently basic pH. This is particularly surprising since thereduction reaction requires the presence of acidic ions.

Advantageously, in order to avoid the presence of a coloured productwhich would impair the purity and colour of the hydrazine, and thus inorder to avoid a rigorous purification step, it is desirable to work ata pH of between 7.2 and 11, preferably between 7.5 and 10.

In order to avoid the presence of tars and heavy products, it ispreferable for the temperature at which step c) is carried out to be atmost equal to 100° C., advantageously to 50° C.

Although this cannot be fully explained, the best results are obtainedwhen the pH of the sulphite/bisulphite solution is buffered with anitrogenous base (such as amines, including anilines) whose pKb isbetween 6 and 11; preferably, the pH is buffered with a nitrogenous basewhose pKb is between 7 and 10.

For economic reasons, the said nitrogenous base is aqueous ammonia.

According to a particularly advantageous embodiment of the presentinvention, step c) is carried out by addition of the said diazoderivative to an initial charge of reductive bisulphite solution.

It is desirable for the pH to be adjusted during step c) such that it isalways close to a preselected value and above 7 and below 11,advantageously below 10.

The process advantageously also includes a step a) of synthesis of thediazo derivative, in particular in order to avoid having to insert thediazo derivative to be reduced.

This step a) of synthesis of the diazo derivative is generally carriedout by the action of a nitrite, advantageously an alkyl or metalnitrite, on an aniline.

Advantageously, the said nitrite is an alkaline nitrite.

In general, the said diazo derivative is a diazonium salt.

The results are more predictable if the aromatic ring bearing the diazofunction is a benzene ring.

The process is particularly advantageous when the said benzene ring, nottaking the diazo function into account, has substituents such that it iselectron-poor overall, or, preferably and, when the benzene ring, nottaking the diazo function into account, is electron-poor due to aninductive effect by at least one electron-withdrawing function. It ispreferred when the two conditions are present together.

It is desirable for the said benzene ring not to have anymesomeric-effect electron-withdrawing substituents.

When the ring bears substituents, the electron-richness of the ring canbe evaluated with the aid of the δ_(p) constants known as the "Hammett"constants. Thus, the sum of the Hammett constants for the substituentson the said benzene ring, not taking the diazo function into account, isbetween 0.1 and 0.7; advantageously between 0.1 and 0.5; preferablybetween 0.1 and 0.35.

For further details regarding the Hammett constants, reference may bemade to the third edition of the book by Professor Jerry March "AdvancedOrganic Chemistry" (pages 242 to 250) published by John Wiley and Sons.

When the benzene ring has only one electron-withdrawing substituent, theelectron-withdrawing substituent does so mainly by means of an inductiveeffect. In addition, it is desirable for the said electron-withdrawingsubstituent to be in a position ortho or para to the diazo function.

These electron-withdrawing substituents are advantageously chosen fromlight halogens (chlorine and/or preferably fluorine), nitrite andperhaloalkyls.

To avoid the degradation of the diazo derivative in the reactionmixture, and thus to avoid having to separate the "diazo" derivativefrom the reaction mixture from which it is obtained, it is desirable forthe process also to include a step b) of reduction of the nitritecontent.

It is also possible to go directly from step a) to step c) provided thatthe insertion is avoided and that the reaction mixture is used quicklyafter step a). This is the case in continuous or semi-continuousprocesses.

Advantageously, the said step b) of reducing the nitrite content iscarried out by placing the reaction mixture obtained in step a) incontact with an agent for reducing the nitrite function, advantageouslyan amide acid, preferably sulphamic acid and/or a derivative thereof.

To complete the process, and if the hydrazine derivative obtained instep c) cannot be used as it is, the process also includes a step d) ofhydrolysis of the sulphone derivative obtained in step c).

This step d) of hydrolysis of the sulphone derivative is advantageouslycarried out in acidic medium, preferably in hydrochloric acid medium.This step d) of hydrolysis of the sulphone derivative is carried out ata temperature of between 20° C. and 70° C., preferably between 40 and60° C.

The non-limiting examples which follow illustrate the invention.

PREPARATION OF 2-FLUOROPHENYLHYDRAZINE

SALIFICATION

400 g of distilled water are placed in a 6-liter jacketed reactor placedunder an inert atmosphere of nitrogen and equipped with a mechanicalstirrer, a condenser, a dropping funnel and a thermometer probe, and 470ml of aqueous 32.5% hydrochloric acid solution are then added over about30 minutes.

The temperature of the solution is brought to 80° C. and 224 g (2 mol)of 2-fluoroaniline (99% pure) are then added over one hour. The reactionmixture is maintained for 1/2 hour under these conditions.

DIAZOTIZATION

The 2-fluoroaniline hydrochloride solution is cooled to 0° C. Thehydrochloride precipitates and a stirrable white broth is obtained.

363 g of aqueous 40% sodium nitrite solution are then added over 2 h 30min and so as not to exceed 3° C. in the broth. The medium becomeshomogeneous and turns an orange-red colour.

After completing for 30 minutes, 97 g of aqueous 12.5% sulphamic acidsolution are added very slowly, in order to destroy the excess sodiumnitrite. The evolution of nitrogen results in the formation of a foam.After completion for 1/2 hour, the medium is drawn down.

REDUCTION

After preparing the reductive solution by addition of 285 g of 28%aqueous ammonia solution to 1547 g of aqueous 40% sodium bisulphitesolution over 1/2 hour and returning the medium to a temperature of 25°C., the diazo solution is added over 2 hours. The reaction medium isthen heated at 50° C. for 30 minutes.

HYDROLYSIS

After this period, 1123 g of aqueous 30% hydrochloric acid solution areadded over about 3 hours. The homogeneous orange-yellow medium ismaintained at 50° C. for 30 minutes.

Note: It is possible at this stage to carry out an extraction withtoluene in order to remove certain heavy products which might have beenformed.

NEUTRALIZATION

The base hydrazine is then released by slow addition of 1250 ml ofaqueous 30.5% sodium hydroxide solution. The medium is then extractedwith 450 ml of toluene, followed by 2×300 ml of toluene. The organicphases are combined.

DESOLVATATION

The desolvatation is carried out by stripping with nitrogen (70° C. at10 mm Hg) after partial distillation of the toluene, i.e. bydistillation on "Luwa" type apparatus, working at 70° C. under 5 mm Hg.

241 g of crude product assaying at 96.1% by HPLC analysis are thusobtained.

Yield of isolated product=92%.

What is claimed is:
 1. Process for the synthesis of arylhydrazine by reduction of a diazo derivative, comprising:c) placing the diazo derivative in contact with a sulphite solution whose pH is at least equal to
 7. 2. Process according to claim 1, wherein said pH is between 7.2 and
 11. 3. Process according to claim 1, wherein said pH is between 7.5 and
 10. 4. Process according to claim 1, wherein the temperature at which step c) is carried out is at most equal to 100° C.
 5. Process according to claim 4, wherein said temperature is at most equal to 50° C.
 6. Process according to claim 1, wherein the pH of the sulphite solution is buffered with a nitrogenous base whose pKb is between 6 and
 11. 7. Process according to claim 1, wherein the pH of the sulphite solution is buffered with a nitrogenous base whose pKb is between 7 and
 10. 8. Process according to claim 7, wherein said nitrogenous base is aqueous ammonia.
 9. Process according to claim 1, wherein step c) is carried out by addition of the said diazo derivative to an initial charge of reductive bisulphite solution.
 10. Process according to claim 1, wherein during step c), the pH is adjusted such that it is always close to a value above 7 and below 11, advantageously below
 10. 11. Process according to claim 1, further comprising a step a) of synthesis of the diazo derivative.
 12. Process according to claim 11, wherein said step a) of synthesis of the diazo derivative is carried out by the action of a nitrite on an aniline.
 13. Process according to claim 12, wherein said nitrite is an alkaline nitrite.
 14. Process according to claim 1, wherein said diazo derivative is a diazonium salt.
 15. Process according to claim 1, wherein the aromatic ring bearing the diazo function is a benzene ring.
 16. Process according to claim 15, wherein said benzene ring is, not taking the diazo function into account, electron-poor owing to an inductive effect by at least one electron-withdrawing function.
 17. Process according to claim 15, wherein said benzene ring, not taking the diazo function into account, has substituents such that it is electron-poor overall.
 18. Process according to claim 15, wherein said benzene ring has no mesomeric-effect electron-withdrawing substituents.
 19. Process according to claim 15, wherein the sum of the Hammett constants of the substituents on the said benzene ring is between 0.1 and 0.7.
 20. Process according to claim 15, wherein said benzene ring has only one electron-withdrawing substituent, said electron-withdrawing substituent being electron-withdrawing by means of an inductive effect.
 21. Process according to claim 15, wherein said electron-withdrawing substituent is located in a position ortho or para to the diazo function.
 22. Process according to claim 1, wherein the electron-withdrawing substituents are chosen from light halogens, nitrite and perhaloalkyls.
 23. Process according to claim 11, further comprising a step b) of reduction of the nitrite content.
 24. Process according to claim 23, wherein said step b) of reduction of the nitrite content is carried out by placing the reaction mixture obtained in step a) in contact with a reducing agent for the nitrite function.
 25. Process according to claim 1, further comprising a step d) of hydrolysis of the sulphone derivative obtained in step c).
 26. Process according to claim 25, wherein step d) of hydrolysis of the sulphone derivative is carried out in acidic medium.
 27. Process according to claim 25, characterized in that the step d) of hydrolysis of the sulphone derivative is carried out at a temperature of between 20° C. and 70° C.
 28. Process for the synthesis of arylhydrazine by reduction of a diazo derivative, comprising:c) placing the diazo derivative in contact with a sulphite solution whose pH is at least equal to 7; wherein the pH of the sulphite solution is buffered with a nitrogenous base whose pKb is between 6 and
 11. 